Ethyl Acetoacetate → Ethyl 4-amino-2,6-dimethylthieno[2,3-b]pyridine-5-carboxylate

HRID 573539Notes

Reaction equation

HRID 573539 reaction equation
[NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].O=[C:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[Sn](Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:8][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[N:1]=[C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=12

Participants

7

Reactant 4

HCID 8868Ethyl AcetoacetateHCID 14798Sodium HydroxideHCID 24287Tin tetrachloride2×HCID 6890562-Amino-5-methyl-3-thiophenecarbonitrile

Product 1

HCID 68323856Ethyl 4-amino-2,6-dimethylthieno[2,3-b]pyridine-5-carboxylateYield 71.5%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 2-amino-5-methyl-3-thiophenecarbonitrile (5 g, 36.2 mmol), ethyl 3-oxobutanoate (5.49 mL, 43.4 mmol) in toluene (200 mL) was added SnCl4 (5.10 mL, 43.4 mmol). The resulting mixture was refluxed for 2 h after which the heater was switched off. SnCl4 (2.123 mL, 18.09 mmol) was added and the mixture refluxed for another 4 h. The solution was cooled and aqueous NaOH (5M) was added until the solution turned basic. Ethyl acetate (100 mL) was added and washed with water (3×30 mL). The organic layer was dried over MgSO4, filtered and solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane afforded the title compound (6.48 g). LCMS (A) m/z: 251 [M+1]+, Rt 0.74 min (acidic).

Workup

  1. temperatureThe resulting mixture was refluxed for 2 h after which the heater
  2. temperaturethe mixture refluxed for another 4 h
  3. temperatureThe solution was cooled
  4. washwashed with water (3×30 mL)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. customsolvent removed in vacuo
  8. customPurification by chromatography on silica gel
  9. washeluting with a gradient of 0-50% ethyl acetate in cyclohexane

Sources & evidence

ORD record
ord-e875407fe22c44b1a3875b180ae4a762
Source dataset
uspto-grants-2015_05
Patent number
US09029545B2

Reaction notes

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